This invention relates to new compounds, to compounds useful for the inhibition of the growth of tumour cells, to a new process for the synthesis of said compounds, to the use of the compounds in the preparation of medicaments for the inhibition of the growth of tumour cells, and to methods for the inhibition of the growth of tumour cells.
Garlic (allium sativum) dietary supplements have a demonstrated ability to reduce the risk of cancer in human beings. The potential chemo-preventative effect of garlic has in the past been the subject of various clinical trials. The outcomes of these trials were contradictory depending on the type of tumour examined and the garlic preparation used. This is due to the fact that crude extracts of garlic contain numerous organosulfur compounds with varying stability and biological activity.
Many of the organosulfur compounds present in garlic have been well characterized. These compounds include allyl disulfides, allyl thiosulfinates and cysteine sulfoxides. Upon maceration of the garlic bulb one of these organosulfides, S-allylcysteine-S-oxide (Olin), is converted to 2-propenethiosulfinate (allicin) by the enzyme allinase. Two molecules of allicin can then combine and rearrange by a thio-Claisen rearrangement to yield an E/Z mixture of 4,5,9-trithiadodeca-1,6,11-triene-9-oxide (E-ajoene and Z-ajoene), the structures of which are represented in Formulae 1.1 and 1.2 respectively. Structurally, ajoene contains interesting sulfoxide (S═O) and unusual vinyl disulfide (═S—S) motifs. Synthesis of ajoene can be conducted in vitro in low yield by thermal decomposition of allicin in an acetone-water mixture.

Ajoene has been shown to offer strong protection against TPA-promoted carcinogenesis on mouse skin, and to strongly inhibit metastasis to the lungs in the B16/BL6 melanoma tumour model in C57BL/6 mice. In one clinical trial topical application of ajoene to the tumours of a group of human patients with either nodular or superficial basal cell carcinoma caused a reduction in tumour size in a large percentage of subjects.
It has also been shown that ajoene is able to induce apoptosis in a number of tumour cell lines including human breast, bladder, colorectal, hepatic, prostate, lymphoma, leukemia and skin. Apoptosis is a form of physiological cell death characterized by chromatin condensation, cytoplasmic blebbing, and DNA fragmentation. Two major pathways mediating drug-induced apoptosis have been characterized. One involves the triggering of cell surface death receptors and the other the targeting of mitochondria without the involvement of a receptor/ligand system. It is hypothesized that ajoene induces apoptosis via the latter pathway. Ajoene has been shown to induce apoptosis and arrest HL60 leukemic cells in the G2/M phase of the cell cycle in a dose-dependent manner. Ajoene-treated leukemia cells undergo a time-dependent reduction in the anti-apoptotic Bcl-2 protein, resulting in the release of cytochrome C and activation of caspase 3. These results support the hypothesis that ajoene-induced apoptosis in leukemia cells proceeds via a mitochondria-dependent caspase cascade.
Ajoene has also been shown to decrease the expression of α4β1 integrin in murine melanoma cells, and to induce complete disassembly of the microtubule network in HL60 cells.